Results Summary

What was the research about?

Multiple sclerosis, or MS, is an illness that affects the central nervous system. Fatigue is a common and disabling symptom of MS.

In this study, the research team wanted to learn how well three commonly used medicines work to help patients with MS feel less fatigued and improve quality of life. The medicines were amantadine, methylphenidate, and modafinil. The team compared these medicines with a placebo. A placebo is a pill with no active ingredients. Using a placebo helps researchers learn if results are due to a medicine or chance.

Patients took each of the medicines and the placebo in a specific order over seven to eight months.

The research team also looked at whether patients took the medicines as prescribed and if they had adverse events. An adverse event is when a medicine causes harm; an example is an allergic reaction.

What were the results?

The three medicines didn’t help patients feel less fatigued or sleepy or improve quality of life better than the placebo.

The percentage of patients who stopped taking each medicine was 6 percent for amantadine, 5 percent for methylphenidate, 8 percent for modafinil, and 3 percent for placebo.

Compared with placebo, more patients who took the medicines reported adverse events. The percentage of patients who reported at least one adverse event was 39 percent for amantadine, 40 percent for methylphenidate and for modafinil, and 31 percent for placebo.

Who was in the study?

The study included 141 adults with MS and fatigue. Of these, 76 percent were White, 14 percent were African American, 10 percent were another race, and 1 percent were Asian; 11 percent were Hispanic. The average age was 47, and 77 percent were women.

What did the research team do?

The research team assigned patients by chance to take the medicines in one of four sequences. Patients started with one medicine and took it for six weeks. Before starting the next medicine, patients stopped taking medicine for two weeks. Patients repeated this process for all three medicines and the placebo.

All patients had a screening visit at one of two health centers; the centers were in Maryland and California. Five weeks after patients started each medicine, they completed online surveys about fatigue, sleepiness, and quality of life. To learn if patients took the medicine as prescribed or had adverse events, the research team contacted patients five times by phone, email, or text during the time they were taking each medicine.

Patients with MS, doctors, an MS specialist, and a member of an advocacy group helped plan the study.

What were the limits of the study?

The study took place at two treatment centers. Patients took medicines for six weeks. Results may differ in other places or with longer-term use of the medicines.

Future research could look at other ways to help patients with MS feel less fatigued.

How can people use the results?

Patients with MS and their doctors can use these results when considering ways to treat fatigue.

How this project fits under PCORI’s Research Priorities
PCORI identified multiple sclerosis (MS) as an important research topic. People with MS, clinicians, and others wanted to learn how different treatment strategies, aimed at changing specific symptoms or the overall course of MS, affect patients’ symptoms and quality of life. To address this issue, PCORI launched an initiative in 2015 on Treatment of Multiple Sclerosis. The initiative funded this research project and others.

Final Research Report

View this project's final research report.

Journal Citations

Article Highlight: Fatigue is one of the most common problems among patients living with multiple sclerosis (MS). Three drugs—amantadine, modafinil, and methylphenidate—are commonly prescribed for reducing fatigue in patients with MS, but conclusive evidence for their effectiveness is lacking. As published in Lancet Neurology, this PCORI-funded study found that these three drugs were no more effective in reducing fatigue in a group of nearly 170 patients with MS than a placebo pill.

Peer-Review Summary

Peer review of PCORI-funded research helps make sure the report presents complete, balanced, and useful information about the research. It also assesses how the project addressed PCORI’s Methodology Standards. During peer review, experts read a draft report of the research and provide comments about the report. These experts may include a scientist focused on the research topic, a specialist in research methods, a patient or caregiver, and a healthcare professional. These reviewers cannot have conflicts of interest with the study.

The peer reviewers point out where the draft report may need revision. For example, they may suggest ways to improve descriptions of the conduct of the study or to clarify the connection between results and conclusions. Sometimes, awardees revise their draft reports twice or more to address all of the reviewers’ comments. 

Peer reviewers commented and the researchers made changes or provided responses. Those comments and responses included the following:

  • The reviewers noted that there are medications often prescribed for patients with multiple sclerosis that could affect patient fatigue and thereby interact with the study treatments. The researchers acknowledged that other medications could affect the severity of patient fatigue but there were no changes in concomitant medications during the study period, so there would be no effect of changes from other medications on study results.
  • The reviewers noted that patients ending medications at the beginning of their study participation might not have had sufficient time to wash out of those medications and asked the researchers to discuss how they accounted for these carry-over effects in their analyses. The researchers added information to the report about medication half-life and their reasoning for a two-week washout period. They explained that two weeks should have been enough time to wash out of the medications that participants were taking and that analyses looking for carry-over effects found none. The researchers concluded that variation in the washout period did not affect the results.

Conflict of Interest Disclosures

Project Information

Bardia Nourbakhsh, MD, MAS
Johns Hopkins University^
Randomized, Double-Blind, Crossover, Placebo-Controlled Trial of Amantadine, Modafinil, and Methylphenidate for Treatment of Fatigue in Multiple Sclerosis

Key Dates

July 2016
February 2021

Study Registration Information

^Bardia Nourbakhsh, MD, was affiliated with The Regents of the University of California when this project was initially awarded.


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Populations Populations PCORI is interested in research that seeks to better understand how different clinical and health system options work for different people. These populations are frequently studied in our portfolio or identified as being of interest by our stakeholders. View Glossary
Intervention Strategy Intervention Strategies PCORI funds comparative clinical effectiveness research (CER) studies that compare two or more options or approaches to health care, or that compare different ways of delivering or receiving care. View Glossary
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Last updated: March 14, 2024